Reaction and temperature control for high power microwave-assisted chemistry techniques

ABSTRACT

A method is disclosed for carrying out microwave assisted chemical reactions. The method includes the steps of placing reactants in a microwave-transparent vessel, placing the vessel and its contents into a microwave cavity, applying microwave radiation within the cavity and to the vessel and its contents while concurrently externally cooling the vessel conductively.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.10/064,261, filed Jun. 26, 2002, now U.S. Pat. No. 6,744,024, which inturn is related to commonly assigned U.S. Pat. Nos. 6,649,889 and6,630,652, and copending and commonly assigned applications Ser. No.10/126,838 filed Apr. 19, 2002; and Ser. No. 09/773,846 filed Jan. 31,2001. These applications are incorporated entirely herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates generally to the field ofmicrowave-assisted chemistry techniques, and in particular relates tomore sophisticated techniques such as chemical synthesis carried out onrelatively small volumes of reactants.

Microwave-assisted chemistry techniques are generally well establishedin the academic and commercial arenas. Microwaves have some significantadvantages in heating certain substances. In particular, when microwavesinteract with substances with which they can couple, most typicallypolar molecules or ionic species, the microwaves can immediately createa large amount of kinetic energy in such species which providessufficient energy to initiate or accelerate various chemical reactions.Microwaves also have an advantage over conduction heating in that thesurroundings do not need to be heated because the microwaves can reactinstantaneously with the desired species.

The term “microwaves” refers to that portion of the electromagneticspectrum between about 300 and 300,000 megahertz (MHz) with wavelengthsof between about one millimeter (1 mm) and one meter (1 m). These are,of course, arbitrary boundaries, but help quantify microwaves as fallingbelow the frequencies of infrared radiation but above those referred toas radio frequencies. Similarly, given the well-established inverserelationship between frequency and wavelength, microwaves have longerwavelengths than infrared radiation, but shorter than radio frequencywavelengths.

Because of their wavelength and energy, microwaves have beenhistorically most useful in driving reactions in relatively large sampleamounts. Stated differently, the wavelengths of most microwaves tend tocreate multi-mode situations in cavities in which the microwaves arebeing applied. In a number of types of chemical reactions, this offerslittle or no disadvantage, and microwave techniques are commerciallywell established for reactions such as digestion or loss-on-dryingmoisture content analysis.

Microwaves, however, have been less successfully applied to smallsamples of materials. Although some chemistry techniques have theobvious goal of scaling up a chemical reaction, in many laboratory andresearch techniques, it is often necessary or advantageous to carry outchemical reactions on small samples. For example, the availability ofsome compounds, may be limited to small samples. In other cases, thecost of reactants may discourage large sample sizes. Other techniques,such as combinatorial chemistry, use large numbers of small samples torapidly gather a significant amount of information, and then tailor theresults to provide the desired answers, such as preferred candidates forpharmaceutical compounds or their useful precursors.

Microwave devices with larger, multimode cavities that are suitable forother types of microwave-assisted techniques (e.g. drying, digestion,etc.) are generally less-suitable for smaller organic samples becausethe power density in the cavity is relatively low and non-uniform in itspattern.

Accordingly, the need for more focused approaches to microwave-assistedchemistry has led to improvements of devices for this purpose. Forexample, in the copending and commonly assigned (CEM Corporation, 3100Smith Farm Road, Matthews, N.C. 28106) U.S. applications referred toabove, and the commercially available devices sold under the assignee'sDISCOVERTM trademark, the assignee of the present invention has provideda single mode focused microwave device that is suitable for smallsamples and for sophisticated reactions such as chemical synthesis.Single mode devices are also available from Personal Chemistry Inc.,Boston, Mass., under the EMRYSTM trademark.

The very success of such single mode devices has, however, createdassociated problems. In particular, the improvement in power densityprovided by single-mode devices can cause significant heating in smallsamples, including undesired over-heating in some circumstances.

Accordingly, some potential advantages remain to be accomplished. Forexample, in chemical synthesis the temperature at which a particularreaction is initiated, run or maintained can be critical to thereaction's success. At various temperatures, products or reactants candegrade undesirably or competing reactions can form compounds other thanthose desired or intended. Because single mode instruments can be soefficient in heating certain materials, this efficiency can occasionallyresult in overheating of synthesis reactants and thus negate theadvantage provided by the single mode instruments. Stated differently,the application of microwaves controls the efficiency of the reactionrather than the bulk temperature of the reactants (and potentially thesolvent, if used). Thus, greater efficiency is gained when a greateramount of microwave energy can be applied without producing an undesiredincrease in the bulk temperature of the materials being irradiated.Thus, although bulk temperature is a factor to be controlled, itrepresents a by-product of the successful use of microwaves rather thana requirement.

Furthermore, most microwave temperature control is often accomplishedusing the duty cycle (the ratio of the duration (time) that a signal ison to the total period of the signal) of the microwave device; i.e.,turning the applied power off and on again on a repeated basis. Thus, inmany cases, when a microwave device is set to run at “50% power”, theapplied power (usually expressed in watts, W) remains the same, and theratio of the duty cycle is reduced; i.e., the “on” portion of the cycleis decreased and the “off” portion is increased. Although such macrocontrol is suitable for larger samples or less sensitive chemicalprocedures such as digestion and moisture analysis, it can be quiteunsatisfactory for carrying out sophisticated chemical reactions or forusing the small samples that are typical for laboratory-scale organicsynthesis techniques.

The duty cycle technique for moderating power, and thus secondarilytemperature, also has the disadvantage of being somewhat inefficient.Stated differently, when the duty cycle is moderated, molecules arebeing intermittently, rather than continuously, excited by microwaveradiation. Thus, instead of being maintained at a particular energylevel or exposed to a continuous power level, the molecules arecontinually cycling between a microwave-excited and a normal or groundstate. As a result, the advantages of using microwaves to apply energyto molecules for the purpose of initiating or accelerating sophisticatedreactions can be compromised.

An extended discussion of the nature and situational disadvantages ofthe duty cycle in microwave assisted chemistry is set forth in commonlyassigned U.S. Pat. No. 6,288,379, the contents of which are incorporatedentirely herein by reference. In particular, a useful backgrounddiscussion is set forth at column 1 line 66 through column 2 line 52.

Thus, although the duty cycle technique has it disadvantages andinefficiencies, it has historically been the only method available toprevent reactions of any type, and particularly sophisticated organicsynthesis reactions, from proceeding above a desired temperature.

Accordingly, the needs exists for a microwave technique that can applygreater amounts of microwave energy without generating the high bulktemperatures that can be undesirable or even fatal to certain reactionsand without sacrificing the advantages of the interaction of themicrowaves with the reactants.

Therefore, it is an object of the invention to provide a microwavetechnique that can remain sensitive enough to control the temperature ofsophisticated organic synthesis reactions, but without sacrificing theadvantages of the interaction of the microwaves with the reactants asoften as possible.

SUMMARY OF THE INVENTION

The invention meets this object with a method of carrying out microwaveassisted chemical reactions in which the method comprises placingreactants in a microwave-transparent vessel, placing the vessel and itscontents into a microwave cavity; and applying a continuous single modeof microwave radiation within the cavity and to the vessel and itscontents while concurrently externally cooling the vessel.

In another aspect, the invention is a method of carrying out microwaveassisted chemical reactions comprising placing reactants in amicrowave-transparent pressure resistant vessel and sealing the vessel,placing the sealed vessel and its contents into a microwave cavity,applying microwave radiation continuously within the cavity and to thevessel and its contents while monitoring the temperature of the vesselor its contents, and while concurrently externally cooling the sealedvessel and its contents.

In yet another aspect, the invention is a method of carrying outmicrowave assisted chemical reactions comprising placing reactants in amicrowave-transparent vessel, placing the vessel and its contents into amicrowave cavity, monitoring the temperature of the vessel or itscontents, applying a continuous single mode of microwave radiationwithin the cavity and to the vessel and its contents until thetemperature reaches a desired setpoint, and concurrently externallycooling the vessel and its contents while applying the continuousmicrowave radiation to maintain the temperature substantially at thesetpoint.

In a further aspect, the invention is a method of carrying out chemicalreactions at specific temperatures comprising applying energy toreactants in a vessel using a source other than conduction heating ofthe vessel or the reactants, while concurrently cooling the vessel byconduction by contacting the exterior of the vessel with a fluid.

In another aspect, the invention is a method of carrying out chemicalreactions comprising applying energy to reactants in a vessel in aninstrument that uses a source other than conduction heating of thevessel or the reactants to heat the reactants, concurrently cooling thevessel in the instrument by providing a flow of conduction fluid againstthe vessel in the instrument, concurrently monitoring the temperature ofthe vessel or its contents in the instrument, and adjusting the heatingsource to maintain the desired temperature at the cooling capacity thatthe instrument can provide to the vessel.

In yet another aspect, the invention is an instrument for carrying outmicrowave assisted chemical reactions. In this aspect, the inventionincludes a microwave cavity, a microwave-transparent vessel in thecavity, a detector for monitoring the temperature of the vessel or itscontents in the cavity, means for applying a continuous single mode ofmicrowave radiation within the cavity and to the vessel and its contentsuntil the temperature reaches a desired setpoint as measured by thedetector, means for concurrently externally cooling the vessel and itscontents while applying the continuous microwave radiation, and meansfor maintaining the temperature substantially at the setpoint whileapplying the microwave radiation.

The foregoing and other objects and advantages of the invention and themanner in which the same are accomplished will become clearer based onthe followed detailed description taken in conjunction with theaccompanying drawings in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of portions of the instrument of thepresent invention.

FIG. 2 is a cross-sectional view of the elements illustrated in FIG. 1.

FIG. 3 is a schematic diagram of the elements of the instrument of theinvention.

FIG. 4 is a schematic diagram of the operation of a processor inaccordance with the present invention.

FIG. 5 is the reaction scheme for an exemplary Negishi reaction carriedout using the method of the present invention.

FIG. 6 is the reaction scheme for an exemplary Diels-Alder reactioncarried out using the method of the present invention.

FIG. 7 is a gas chromatogram of a Diels-Alder reaction carried outconventionally between furan and diethylacetylene dicarboxylate to formthe bridged cyclohexadiene.

FIG. 8 is the mass spectrum of the product peak from FIG. 7.

FIG. 9 is the gas chromatogram of the same Diels-Alder reaction, butcarried out according to the present invention.

FIG. 10 is the mass spectrum of the product peak of FIG. 9.

FIG. 11 is another version of the gas chromatogram illustrated in FIGS.7 and 9, but with the area under the peaks integrated to calculateyields.

FIG. 12 is the gas chromatogram for a Negishi reaction carried outbetween 2-chloropyridine and 2-methylphenyl zinc iodide carried outconventionally.

FIG. 13 is the mass spectrum of the product peak of FIG. 12.

FIG. 14 is the gas chromatogram of the same Negishi reaction carried outusing the method of the invention.

FIG. 15 is the mass spectrum of the product peak/fraction from FIG. 14.

FIG. 16 is another reproduction of the gas chromatogram of FIGS. 12 and14, with one of each being integrated in order to calculate yields.

DETAILED DESCRIPTION

In its broadest aspect, the present invention is a method of carryingout chemical reactions, particularly sophisticated or sensitive chemicalreactions at specific temperatures, by applying energy to reactants orreactants in a vessel using a source other than conduction heating whileconcurrently cooling the vessel by conduction by contacting the exteriorof the vessel with a fluid. The net result is to maintain a desiredtemperature while still having capability of applying significantamounts of energy other than by heat conduction.

In a strict sense, the term “reagent” refers to “a substance used in areaction for the purpose of detecting, measuring, examining, oranalyzing other substances,” Lexis, Hawley's Condensed ChemicalDictionary, 12^(th) Ed. (1993), Van Nostrand Reinhold Company; while theterm “reactant” refers to, “a substance that reacts with another one toproduce a new set of substances (products),” McGraw-Hill Access Science(www.accesscience.com). Although these terms are frequently usedinterchangeably, they will be used properly herein.

In preferred embodiments, the step of applying energy comprises exposingthe vessel and the reactants—and not necessarily the solvents—toelectromagnetic radiation, which in turn is selected from the groupconsisting of microwaves, infrared radiation, radiation in the visibleportion of the spectrum, and ultraviolet radiation, with microwavesbeing most preferred. The nature and frequencies of each of these setsof electromagnetic radiation are well understood and will not beotherwise discussed in detail herein.

In this aspect, the method can further comprise directing a flow of airfrom the instrument to the vessel to provide the flow of conductionfluid. As discussed elsewhere herein, the flow of air can be from a fan,from a source of compressed air, from a regulator, or from any otherappropriate source that does not otherwise interfere with the heating orthe reaction itself.

Although the term “vessel” is used herein, it will be understood thatthe invention is not limited to sealed or unsealed vessels of anyparticular size or shape. Additionally, the term vessel can includeother physical arrangements for handling the reactants, includingflow-through systems.

In more preferred embodiments, the method additionally comprisesconcurrently monitoring the temperature of the vessel or its contents inthe instrument, and adjusting the heating source to maintain the desiredtemperature at the cooling capacity that the instrument can provide tothe vessel. The temperature is preferably monitored using a device ormethod that does not interfere with the concurrent heating and coolingsteps. Thus, in preferred embodiments, temperature measurement is oftencarried out optically, most preferably by using an infrared (IR)temperature sensor. An IR sensor is particularly useful when thefrequencies being applied to supply energy to the reactants are otherthan IR, because the infrared sensor measures radiation emitted by thevessel or its contents and does not need to be in direct contact withthe vessel. Accordingly, it can be positioned in a spot that does notcause interference with electromagnetic radiation and does not interferewith the cooling flow of fluid, usually air.

Thus, temperature control can be carried out by varying the coolingwhile applying the microwave radiation in a constant manner, or byvarying the application of microwaves while providing a constant coolingflow.

In another aspect, the method comprises placing reactants in amicrowave-transparent vessel, potentially but not necessarily includingplacing the reactants in pressure-resistant vessels which can be sealedprior to the application of microwave radiation. The vessel and itscontents are then placed into a microwave cavity and a continuous singlemode of microwave radiation is applied within the cavity to the vesseland its contents while concurrently externally cooling the vessel.

Because of the nature of microwaves, which follow well understood lawsof wave propagation, the production of a single mode is most oftenaccomplished by designing a cavity having a geometry that supports asingle mode. As used herein and as generally well-understood in thisfield, the term “mode” refers to the permitted electromagnetic fieldpattern within a cavity.

Microwave modes are generally referred to by the TE_(n,l,m) designation(TM for the magnetic field) where the subscripts refer to the number ofnulls in the propagated direction. Cavities that can support singlemodes are set forth in the art and are generally understood by thosefamiliar with microwaves and their propagations. An exemplary cavity forpropagating a single mode of microwave radiation is set forth in thepreviously incorporated applications. The invention is not, however,limited to single mode techniques or cavities.

The application of a continuous microwave radiation is preferablyaccomplished using a resonant inverter switching power supply as setforth in previously incorporated U.S. Pat. No. 6,288,379. Thus, the term“continuous” is used herein in a descriptive rather than an absolutesense and refers to applying radiation from a source while driving thesource at a frequency greater than 60 hertz. More preferably, the sourceis driven at a frequency greater than 600 hertz, even more preferably atgreater than 6,000 hertz and most preferably at frequencies betweenabout 10,000 and 250,000 hertz. As described in the '379 patent, thispermits the power to be applied at a more even level over a longerperiod of time than in conventional devices which operate on 50 cycle(typical in Europe) or 60 cycle alternating current (standard in theUnited States). Any appropriate microwave source can be used that isconsistent with the other aspects of the invention and typicallycomprises a magnetron, a klystron, or a solid state source, such as aGunn diode.

The method can also include the step of using various robotic transfersto both place the reactants in a microwave transparent vessel and toplace the vessel and contents into a microwave cavity.

Because one of the goals of the invention is to provide careful controlof reaction temperature, the step of cooling the vessel and its contentsgenerally comprises directing an airflow over (around) the vessel at arate (typically measured as volume per unit time or a given pressure)sufficient to maintain the vessel and its contents at a desiredtemperature. For typical organic reactions that are taking place in therange of between about 40° C. and 250° C., an airflow directed orgenerated at between about 1 and 80 pounds per square inch (psi) hasbeen found to be appropriate. From a functional standpoint, the airflowis sufficient to provide cooling while less than that which would causeundesired or unnecessary buffeting or other mechanical problems, or thatwould lower the bulk temperature below a point that was desired for aparticular reaction scheme or other purpose.

The method can also comprise varying the rate and degree of cooling, forexample by changing the rate of airflow in response to the measuredtemperature, a step which is preferably carried out while the microwavesare being applied and the vessel is being externally cooled.

In another aspect, the method comprises placing reactants in a microwavetransparent vessel, placing the vessel and its contents into a microwavecavity, continuously monitoring the temperature of the vessel or itscontents, and applying a continuous single mode of microwave radiationwithin the cavity and to the vessel and its contents until thetemperature reaches a desired set point, and then concurrentlyexternally cooling the vessel and its contents while applying thecontinuous microwave radiation to maintain the temperature substantiallyat the set point. Most preferably, the cooling step comprises coolingthe vessel with a fluid from a fluid source and the step of applying themicrowave radiation comprises maximizing the microwave power at thecapacity of the cooling source while maintaining the temperaturesubstantially at the set point.

Stated differently, the goal is to apply as much microwave power(energy) to the reactants as possible while avoiding exceeding a desiredset point temperature. Given that the capacity of the cooling systemwill be a determining factor in how much heat can be transferred awayfrom the vessel and the reactants, the microwave power is maintained ashigh as possible, consistent with the cooling capacity of the coolingdevice associated with the microwave instrument.

Because chemical reactions can be carried out in stages, often desirablyso, the method can further comprise changing the set point at a desiredtime or stage of the reaction and then again carrying out the steps ofapplying microwave radiation and external cooling to reach and maintainthe temperature at the new set point.

Thus, for reactants (as opposed to solvents) the method of the presentinvention provides an enhanced reaction rate at any given temperature ascompared to a thermally or conductively heated reaction. This resultsfrom the direct molecular heating provided by microwave radiation, whichin turn can produce superheated molecules. Some of that energy will, ofcourse, transfer to the solution and create the bulk temperature that ismeasured. Because of the cooling step, the invention offers similaradvantages over more conventional microwave techniques that aggressivelydecrease the applied power in order to control the bulk temperature.

Stated differently, a reaction carried out at 150° C. that is initiatedand maintained by conductive heating will proceed at a given rate. Ifthe temperature of the same reaction is maintained at 150° C. usingmicrowave heating, the rate will be enhanced because of the directmolecular heating. Even better, however, using the invention, a reactioncarried out at 150° C. using microwave radiation and proactive coolingwill have the highest rate because it provides the greatest opportunityto maximize the microwave energy being applied directly to thereactants.

As known to those familiar with microwave radiation andmicrowave-assisted chemistry, in the microwave frequency ranges, thepolar (or ionic) molecules will try to constantly align with a rapidlychanging electric field. This movement creates the bulk heat. Theresulting bulk temperature can be disadvantageous when heat sensitivereactions are carried out, or reactions using heat sensitive reactantsor that create heat sensitive products. Proteins are an example ofmolecules that tend to be overly sensitive to high temperatures, andthus hard to heat moderately using microwaves, absent the cooling stepof the invention.

The method of the invention is particularly useful with cross-couplingreactions that produce carbon-carbon bonds in complex organic synthesessuch as the development of pharmaceutical products. These include theHeck, Kharash, Negishi, Stille, or Suzuki reactions which are well knownin the art. In general, diaryl compounds are synthesized by a number ofcatalytic cross-coupling reactions from arylhalides or triflates andarylmetal reagents; for example, Grignard reagent (Kharasch reaction),arylzinc reagent (Negishi reaction), palladium-catalyzed vinylicsubstitution (Heck reaction), aryltin reagent (Stille reaction),arylboron reagent (Suzuki reaction), arylsilyl reagent, etc.

For example, in the Negishi reaction an aryl chloride is reacted with anaryl zinc halide. The reaction is palladium catalyzed intetrahydrofuran. Two competing reactions can occur. In the undesiredcompeting reaction, the aryl zinc halide simply substitutes with itselfto provide a biaryl molecule. Instead, the preferred reaction is toproduce a substituted biaryl compound with zinc dihalide as thebyproduct. In comparative tests, and using the method of the invention,the desired reaction that produced the disubstituted aromatic compoundhad a much higher yield than when the reaction was carried out withoutthe cooling step. This results, of course, from control of thetemperature to prevent the competing reaction from progressing.

Stated differently, the invention can drive a microwave activatedreaction complex, rather than a thermally-driven activated competingreaction, to produce a desired reaction in a manner that would bedifficult using conventional conduction heating.

Similar advantages are expected for Diels-Alder reactions (i.e., thereaction of unsaturated carbonyl compounds with conjugated dienes).

The drawings illustrate a preferred instrument suitable for carrying outthe method steps of the present invention.

FIG. 1 is a perspective view of a presently preferred embodiment ofcarrying out the method of the present invention. FIG. 1 illustrates amicrowave cavity broadly designated at 10, which is of the same type asthe cavity described and claimed in copending and previouslyincorporated '914; '628; '838; and '846 applications. Because the natureof the cavity and the operation of the entire instrument is clearly setforth in these applications, the cavity will not be described in detailherein other than to explain the invention. FIG. 1 also shows a portionof the waveguide 11 into which a microwave source propagates microwavesfor transmission into the cavity 10. A reaction vessel 12 is positionedin the cavity 10 in a manner described in the incorporated applications.Thus, it will be understood that although FIG. 1 shows the reactionvessel 12 as being suspended without evident support, in reality it ismaintained in place by the additional structure (preferably anattenuator) described in those applications.

In the preferred embodiment, the cooling step is carried out bydirecting a flow of cooling fluid, preferably air, from the coolingnozzle 13 over and around the vessel 12. In turn, the cooling fluidreaches the cooling nozzle through the illustrated tubing 14, the flowof which is controlled by the solenoid 15. As set forth with respect tothe method aspects of the invention, appropriate software can be used tocontrol the solenoid and in turn, the flow of fluid through the tubing14 to adjust the amount of cooling flow of fluid from the cooling nozzle13 into the cavity 10 and against the reaction vial 12. The nature andoperation of all of these elements is well understood in this and otherarts, and need not be discussed in detail herein other than to describethe invention.

Some additional elements illustrated in FIG. 1 include an inlet fitting16 for connecting the solenoid 15 and the tubing 14 to a source ofcooling fluid whether compressed air, or some other gas. The tubing 14is connected to the cooling nozzle 13 through the fitting 17 and inpreferred embodiments the cooling nozzle is placed within an exhausthousing 20 beneath the cavity 10. FIG. 1 also illustrates that in thepreferred embodiment, which is a version of the DISCOVER™ tool referredto earlier herein, the microwave cavity 10 has circular or cylindricallyshaped portions, and includes a plurality of slots 21 through whichmicrowaves propagate as they enter from the waveguide 11. In theillustrated embodiment, the waveguide 11 is generally rectangular inshape and is formed of several perpendicularly arranged walls of whichthe largest illustrated in FIG. 1 are the walls 22 and 23. Portions ofthe top wall 24 and a bottom wall 25 are also illustrated in FIG. 1. Acylindrical housing 26 adjacent the bottom of the cavity 10 is describedin more detail in the incorporated applications, but generally serves asa housing for a temperature-sensing device such as an infraredtemperature-measurilng device.

FIG. 2 is a cross-sectional view of the same portion of the preferredinstrument as illustrated in FIG. 1. All of the elements are the sameand maintain the same reference numerals. FIG. 2, however, also includesthe arrows 27 that help illustrate the direction of flow of the coolingfluid.

In another aspect the invention is an instrument for carrying out themicrowave assisted chemical reactions according to the method of theinvention. In this aspect, the invention comprises a microwave cavity, amicrowave transparent vessel in the cavity, a detector for monitoringthe temperature of the vessel or its contents in the cavity, means forapplying a continuous single mode of microwave radiation within thecavity and to the vessel and its contents until the temperature reachesa desired set point as measured by the detector, means for concurrentlyexternally cooling the vessel and its contents while applying thecontinuous microwave radiation, and means for maintaining thetemperature substantially at the set point while applying the microwaveradiation.

FIG. 3 schematically illustrates some of these elements and complimentsthe illustration of FIGS. 1 and 2. FIG. 3 illustrates the cavity, againdesignated at 10, into which the reaction vessel 12 (FIG. 1) can beplaced. A source 30 of microwave radiation is in communication with thecavity 10 as designated by the arrow 31. This path of communicationgenerally includes the waveguide 11, portions of which are illustratedFIGS. 1 and 2. The temperature detector is designated at 32 and inpreferred embodiments comprises an infrared temperature detector asdescribed in the incorporated applications. As set forth therein, aninfrared detector is particularly useful because it detects frequenciesdifferent than those being applied from the source 30 into the cavity10. Additionally, an infrared detector does not require actual physicalcontact with the item for which the temperature is being measured.Appropriate infrared temperature detectors are commercially available,well understood, and quite durable and thus meet a number ofrequirements for this use.

FIG. 3 also illustrates that in preferred embodiments the instrumentcomprises a processor 33 that is in signal communication (i.e.,electrical communication) with the detector 32. FIG. 3 illustrates thisusing the data symbol 34 to illustrate the flow of temperatureinformation from the detector 32 to the processor 33. The term“processor” as used herein refers to devices that can store instructionsand execute them. In preferred embodiments the processor is asemiconductor microprocessor, the nature and operation of which arewidely understood in this and other arts. Such processors are alsoreferred to as “CPU's” (central processing unit). The processorpreferably is in communication with an input device (most typically akeyboard or keypad) for providing the processor with data selected fromthe group consisting of microwave power levels, durations of microwaveapplication and setpoint temperatures.

As described with respect to FIGS. 1 and 2, the means for cooling thevessel 12 and its contents preferably comprises a source of coolingfluid and a fluid communication path from the source to the cavity 10.As illustrated in FIGS. 1 and 2, and schematically in FIG. 3, the fluidcommunication path includes the tubing 14 illustrated in FIG. 1 andschematically represented in FIG. 3 along with the cooling nozzle 13 andthe fitting 17. In preferred embodiments, the instrument furthercomprises the solenoid flow controller 15. As illustrated in FIG. 3, theprocessor 33 controls the flow solenoid 15 to moderate the flow of thefluid, typically air, from the fluid source 35 to the cavity 10. Thus,the flow solenoid 15 is in signal communication with the processor 33,which is also in signal communication with the temperature detector 32.In this manner, the flow solenoid 15 moderates the flow of fluid fromthe fluid source 35 to the cavity 10 in response to signals from theprocessor 33. In turn, the signals from the processor 33 to the flowsolenoid 15 are based on the data 34 received from the temperaturedetector 32 and forwarded to the processor 33. The processor can beprogrammed or used in any appropriate manner, and FIG. 3 illustrates theuse of a manual input 36 such as a keyboard or keypad as noted above.

FIG. 4 is another schematic diagram that shows the logic sequence of theprocessor 33. FIG. 4 again illustrates the cavity 10, the source offluid (typically compressed air) 35, the flow solenoid 15 between thefluid source 35 and the cavity 10, and the temperature detector 32. Theprocessor 33 is indicated by the dashed rectangle and includes twodecision points, a process capability, and the input device 36. Thefirst decision point is designated at 40 in which the processorevaluates whether the temperature measured by the detector 32 is at thedesired set or control point. If the temperature is at the controlpoint, no action is taken. If the temperature is not at the controlpoint, the processor uses the cooling algorithm 41 to control the flowsolenoid 15 to moderate the flow of air from the source 35 through thesolenoid 15 to the cavity 10. In a similar manner, the processor has thecapability of evaluating whether the power is at the desired level asindicated by the decision parallelogram 42.

In this manner, the invention provides the capability to enter atemperature setpoint into the processor, then apply power to thereactants. When the reactants reach the setpoint temperature, theprocessor can instruct the cooling to begin by controlling the flowsolenoid 15. As set forth herein, this permits a greater amount ofmicrowave power to be applied to the reaction because temperaturecontrol is carried out in a manner other than reducing the applied poweror extending the off portion of the duty cycle. When the reaction iscomplete (which can also be a pre-set reaction time), the processor caninstruct the cooling to continue until the vessel and its contents reacha desired lower temperature, typically a temperature at or near roomtemperature.

The nature and instructions required to provide such information to aprocessor of this type are generally well understood in this and otherarts and can be practiced by those of ordinary skill in this art withoutundue experimentation.

As set forth earlier, control systems of this type are generally wellunderstood and can be selected and practiced by those of ordinary skillin this and other arts without undue experimentation. Reasonablediscussions of control systems of various types is set forth in Dorf,THE ELECTRICAL ENGINEERING HANDBOOK, 20th Ed., CRC Press (1997).

EXAMPLES

Exemplary microwave reactions were carried out using a CEM DISCOVER™System single-mode microwave instrument from CEM Corporation, Matthews,N.C. All reactions were performed in specially designed Pyrex pressuretubes equipped with a stir bar and were sealed with a Teflon/siliconseptum. All gas chromatograms (GC) and mass spectra (MS) were obtainedusing a PerkinElmer AutoSystem XL GC/TurboMass MS system.2-Chloropyridine, 1-methylphenylzinc iodide, furan, and diethylacetylenedicarboxylate were all purchased from Aldrich and were used as received.The organozinc iodide reagent came as a 0.5 M solution in THF in aSure-Seal bottle. Pd(P(t-Bu)₃)₂ was purchased from Strem Chemicals andwas used as received.

Negishi Reaction: Preparation of 2-o-Tolylpyridine. 2-Chloropyridine(100 mg, 0.88 mmol), Pd(P(t-Bu)₃)₂ (23 mg, 0.044 mmol), and1-methylphenylzinc iodide (2.7 mL, 1.3 mmol) were mixed together in areaction tube. The tube was sealed and the contents were irradiated for10 min (not including a 1 min ramp time) at 50 W of power and 180° C. Inone reaction, simultaneous cooling was administered. The power wasincreased slowly to 75 W in 5-watt increments and the bulk temperatureremained around 150° C. The crude mixture was immediately purified bycolumn chromatography (10:1 hexanes/EtOAc), which yielded a pale yellowliquid. This was analyzed by GC/MS. The MS of this compound was inagreement with the spectrum in the NIST MS library. This compound hasbeen previously prepared and spectroscopically characterized; e.g. Dai,C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, pp. 2719-24. FIG. 5illustrates the reaction scheme.

Diels-Alder Reaction: Preparation of 1,2-dicarboxylic acid diethylester-3,6-epoxycyclohexa-1,4-diene. Furan (100 mg, 0.11 mL, 1.5 mmol)and diethylacetylene dicarboxylate (250 mg, 0.24 mL, 1.5 mmol) weremixed together in a reaction tube. The reaction was performed neat, andwith no solvent present. The tube was sealed and the contents wereirradiated for 5 min (not including a 5 min ramp time) at 100 W of powerand 200° C. In one reaction, simultaneous cooling was administered. Thepower was increased slowly to 250 W in 10-watt increments and the bulktemperature remained around 120° C. The crude mixture was a dark red oilin the cooled reaction while it was a dark brown tarry substance in thereaction that was not cooled. Both were analyzed by GC/MS. The MS ofthis compound was in agreement with the spectrum in the NIST MS library.FIG. 6 illustrates this reaction scheme.

FIGS. 7 through 16 represent experimental confirmation of the success ofthe method of the invention in comparison to more conventional microwavetechniques. The figures are either gas chromatograph fraction plots ormass spectra of particular compounds. The theory and operation of gaschromatography and mass spectrometry are well understood in the art, canbe practiced by those of ordinary skill in this art, and will not beotherwise discussed in detail herein other than to illustrate thepresent invention.

FIG. 7 is the gas chromatograph of the compounds present after carryingout the above-described Diels-Alder reaction under conventionalmicrowave heating (i.e., without the cooling step of the presentinvention). In the Diels-Alder reaction represented by FIG. 7, thetemperature reached as high as 200° C. (heat being a generally expectedbyproduct of the Diels-Alder reaction) and thus the microwave powerapplied was limited to 100 watts.

In FIG. 7, the abscissa (x-axis) represents time and thus the individualpeaks demonstrate the time at which each fraction exited the column. Theordinate (y-axis) is an arbitrary measure for which 100% represents thelargest fraction collected from the column in that particular samplerun. Each of the peaks is labeled with two numbers; e.g.11.08 and 125for the largest peak in FIG. 7. The first number (11.08) is theretention time for the particular fraction; i.e., the time in minutesafter injection at which the fraction exited the column. The secondnumber (125) is obtained from the mass spectra that is carried out oneach fraction as it exits the chromatography column and represents themolecular weight of the largest fragment that the mass spectrometerdetects from that particular fraction. In FIG. 7, the peak at 11.08minutes represents the starting material, and the peak at 16.28 minutesrepresents the desired product, 1,2-dicarboxylic acid diethylester-3,6-epoxycyclohexa-1,4-diene. The mass spectra confirms theidentity of the compound of the corresponding peak and specificallyconfirms that the peak at 16.28 minutes is the desired product.Accordingly, all of the remaining peaks represent unreacted startingmaterials or undesired byproducts. In particular, it will be noted thatthe byproduct fraction that exits the column at 14.40 minutes (adisubstituted furan in which the substitution groups are ethyl ester) ispresent in an amount slightly greater than the amount of the desiredproducts (as confirmed by the integrations discussed with respect toFIG. 11). Thus, FIG. 7 shows that when the Diels-Alder reaction betweenthese compounds is carried out under microwave radiation but withoutcooling, the results include a large amount of unreacted startingmaterial, a large amount of byproduct, and a relatively small, at leastas compared to the starting materials, yield of product.

FIG. 8 is the mass spectrum of the fraction collected at 16.28 minutesas illustrated in FIG. 7.

FIG. 9 is the gas chromatograph of the same Diels-Alder reactionrepresented by the chromatograph of FIG. 7, but with the cooling step ofthe invention included. As a first point of comparison, when running theDiels-Alder reaction in conjunction with the present invention, thecooling maintained the temperature at between about 100° and 125° C.which allowed the microwave power to be increased to 250 watts.

As another point of comparison, it will be immediately observed that thechromatograph of FIG. 9 is extremely clean in that the dominant fractionobtained is the desired product which exits the column at the same time(within experimental uncertainty) as it did in FIG. 7. It will also beobserved that the desired product and its fraction are present in a muchgreater amount than the starting material illustrating a higher yieldfrom the reaction. Additionally, the lack of other byproduct peaksillustrates that the reaction proceeded more successfully in the desiredmanner than it did in absence of the invention.

FIG. 10 is the mass spectrum of the product peak from FIG. 9 and againconfirms that the fraction was the desired product. Although a slightlydifferent number of minutes are plotted in FIG. 10 as compared to FIG.8, it will be immediately observed that the fragment peaks fall at thesame positions (molecular weights) and thus confirm the identity of thedesired compound in each case.

FIG. 11 is another set of the gas chromatographs of FIGS. 7 and 9, butwith each chromatograph reproduced twice, once with the area under thepeak integrated. Accordingly, FIG. 11A represents the Diels-Alderreaction carried out conventionally, and showing the area integratedunder the peaks. FIG. 11B is identical to FIG. 11A but without theintegration.

In the same manner, FIG. 11C is the same gas chromatograph as FIG. 9with the peaks integrated, and FIG. 11D is the same as FIG. 11C butwithout the integration of the peaks.

In FIGS. 11A and 11C, the peaks are identified by three numbers. Thefirst two are the same as previously noted; i.e. the retention time ofthe fraction in the column, and the molecular weight of the dominatingfragment in the mass spectrum. The third number is the area under thepeak (in arbitrary units). Accordingly, the yield of any product,byproduct, or even of remaining starting material, can be obtained bydividing the area under its peak by the total area under all of thepeaks. In this manner, the integration results of FIG. 11A demonstratethat the yield of the desired product (the fraction exiting at 16.28minutes) using microwave heating without the cooling step of theinvention is only 21%. In comparison, however, FIG. 11C shows that theyield of the desired product is 76% using the method of the invention.

FIG. 12 is the gas chromatograph of the Negishi reaction carried outbetween 2-chloropyridine and 2-methylphenyl zinc iodide to form2-o-tolylpyridine. FIG. 12 represents the gas chromatograph when thereaction was carried out using microwave radiation, but not the coolingstep. In doing so, the temperature quickly reached as high as 180° C.which required maintaining the microwave power being applied to 50 wattsor less. In FIG. 12, the fraction exiting the column at 17.43 minutes(dominant fragment weight 168) represents the desired product. The peakexiting at 6.9 minutes representing the 2-chloropyridine startingmaterial and the peak representing the fraction exiting at 16.27 minutesrepresents the undesired 2,2′-dimethylbiphenyl byproduct. Several otherpeaks representing undesired byproducts are likewise present in thechromatograph of FIG. 12. Thus, although FIG. 12 represents a reactionin which the desired product is the largest fraction, its presence isalmost entirely matched by the amount of undesired byproducts, alongwith significant amounts of starting material and other undesiredbyproducts.

FIG. 13 is the mass spectrum of the fraction that exited the columnrepresented by FIG. 12 at 17.43 minutes and confirms the identity of thedesired 2-o-tolylpyridine product.

FIG. 14 represents the same Negishi reaction using the same startingmaterials to obtain the same desired product, but carried out using thecooling method of the present invention. The cooling enabled thetemperature to be maintained at 150° C. or less, which in turn allowedthe maximum microwave power to be increased to 75 watts. The products ofthe reaction represented by FIG. 14 were run through a slightlydifferent gas chromatography column, thus giving retention times thatare similar, but not identical, to those in FIG. 12. The molecularweight associated with the dominant fragment in each fraction, however,remained the same and thus the same starting materials and byproductscan be identified. Accordingly, it will be seen that the2-chloropyridine starting material with its characteristic 9 fraction ispresent in a much smaller relative amount in FIG. 14 than it was in FIG.12. Similarly, the undesired 2,2′-dimethylbiphenyl byproduct with thecharacteristic fragment at 167 is likewise minimal, as are the otherbyproducts.

FIG. 15 is the mass spectrum of the fraction that exited the columnrepresented by FIG. 14 at 19.29 minutes, and as in the case of FIG. 13,confirms that the desired product is that fraction.

FIG. 16 is analogous to FIG. 11 and includes four subparts, A-D, two ofwhich (A and C) include integration of the peaks of the gaschromatograph fractions for the comparative reactions. Accordingly,FIGS. 16A and 16B represent the gas chromatograph results for theNegishi reaction carried out with microwave radiation, but withoutcooling, and FIGS. 16C and 16D represent the same reaction carried outusing the cooling step of the present invention. As with respect to FIG.11, each peak is characterized by three numbers, the first being theretention time, the second being the molecular weight of the dominantfragment in the fraction as determined by mass spectroscopy, and thethird being arbitrary units of area under the peak. Using the sameanalysis as described with respect to FIG. 11, the yield of the desiredproduct in FIG. 16A (the fraction at 17.43 minutes) using conventionalmicrowave techniques is 36.5 percent. In FIG. 16C, and using 1 themethod of the invention, the yield is 66 percent.

These results can also be summarized in tabular format:

Time Temperature Power Reaction (Minutes) (Degrees C.) (Watts) YieldDiels-Alder 5 200 100 21 (Conventional Microwave) Diels-Alder 5 120 25076 (Invention) Negishi 10 180 50 36.5 (Conventional Microwave) Negishi10 150 75 66 (Invention)

In the drawings and specification there has been set forth a preferredembodiment of the invention, and although specific terms have beenemployed, they are used in a generic and descriptive sense only and notfor purposes of limitation, the scope of the invention being defined inthe claims.

1. A method of carrying out chemical reactions at specific temperatures,the method comprising: applying energy to reactants in a vessel using asource other than conduction heating of the vessel or the reactants;while concurrently cooling the vessel by conduction by contacting theexterior of the vessel with a fluid; and while concurrently monitoring atemperature selected from the group consisting of the temperature of thevessel, the temperature of the contents and combination thereof.
 2. Amethod according to claim 1 wherein the step of applying energycomprises exposing the vessel and reactants to electromagnetic radiationselected from the group consisting of microwaves, infrared, visible andultraviolet radiation.
 3. A method according to claim 1, wherein thestep of concurrently cooling the vessel further comprises directing aflow of air from an instrument to the vessel.
 4. A method according toclaim 3 comprising directing the flow of air from a fan.
 5. A methodaccording to claim 3 comprising directing compressed air to the vessel.6. A method of carrying out chemical reactions, the method comprising:applying energy to reactants in a vessel in an instrument that uses asource other than conduction heating of the vessel or the reactants toheat the reactants; concurrently cooling the vessel in the instrument byproviding a flow of conduction fluid against the vessel in theinstrument; concurrently monitoring the temperature of the vessel or itscontents in the instrument; adjusting the heating source to maintain thedesired temperature at the cooling capacity that the instrument canprovide to the vessel.
 7. A method according to claim 6 wherein the stepof applying energy comprises exposing the vessel and reactants toelectromagnetic radiation.
 8. A method according to claim 7 comprisingexposing the vessel and reactants to electromagnetic radiation havingfrequencies selected from the group consisting of microwaves, infrared,visible and ultraviolet radiation.
 9. A method according to claim 6wherein the step of providing the flow of conduction fluid comprisesdirecting a flow of air from the instrument to the vessel.
 10. A methodaccording to claim 9 comprising directing the flow of air from a fan.11. A method according to claim 9 comprising directing compressed air tothe vessel.
 12. A method according to claim 6 wherein the step ofmonitoring the temperature comprises monitoring the temperature withoutinterfering with the concurrent heating and cooling steps.
 13. A methodof carrying out multi-step chemical reactions, the method comprising:applying energy to reactants in a vessel in an instrument that uses asource other than conduction heating of the vessel or the reactants toheat the reactants to a first set point; concurrently cooling the vesselin the instrument by providing a flow of conduction fluid against thevessel in the instrument; thereafter applying energy to the reactants inthe vessel to heat the reactants to a second set point to therebyinitiate a second step reaction; concurrently cooling the vessel in theinstrument by providing a flow of conduction fluid against the vessel inthe instrument; concurrently monitoring the temperature and adjustingthe heat source during each step to thereby maintain the desiredtemperature by maximizing the microwave power at the capacity of thecooling source.
 14. The method of claim 13 further comprising the stepof applying energy to the reactants in the vessel to heat the reactantsto a third set point to thereby initiate a third step reaction.
 15. Themethod of claim 13 wherein the step of applying energy comprisesexposing the vessels and reactants to electromagnetic radiation.
 16. Amethod according to claim 15 comprising exposing the vessel andreactants to electromagnetic radiation having frequencies selected fromthe group consisting of microwaves, infrared, visible, and ultravioletradiation.
 17. A method according to claim 13 wherein the steps ofproviding the flow of conduction fluid comprises directing a flow of airselected from the group consisting of compressed air and air from a fanfrom the instrument to the vessel.
 18. A method according to claim 13wherein said second set point is lower than said first set point.
 19. Amethod according to claim 14 wherein each of said set points representsa temperature different from each of said other set points.
 20. A methodaccording to claim 13 wherein the step of monitoring the temperaturecomprises monitoring the temperature without interfering with theconcurrent heating and cooling steps.